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一种GAD1抑制剂通过Wnt/β-连环蛋白信号通路抑制骨肉瘤生长。

A GAD1 inhibitor suppresses osteosarcoma growth through the Wnt/β-catenin signaling pathway.

作者信息

Jian Changchun, Wang Ben, Mou Hai, Zhang Ye, Yang Chaohua, Huang Qiu, Ou Yunsheng

机构信息

Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.

Orthopedic Laboratory of Chongqing Medical University, Chongqing, 400016, China.

出版信息

Heliyon. 2024 May 17;10(10):e31444. doi: 10.1016/j.heliyon.2024.e31444. eCollection 2024 May 30.

DOI:10.1016/j.heliyon.2024.e31444
PMID:38803976
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11128529/
Abstract

BACKGROUND

As a marker of the GABAergic system, the expression of glutamate decarboxylase 1 (GAD1) is mainly restricted to the central nervous system. Emerging studies have shown that aberrant expression of GAD1 in tumor tissues may promote tumor cell growth. The role of GAD1 in the development of osteosarcoma (OS) remains unclear, so this study sought to investigate the expression status of GAD1 and the effect of its specific inhibitor 3-mercaptopropionic acid (3-MPA) on OS.

METHODS

The R2 database was used to analyze the relationship between the expression of GAD1 and clinical prognosis in OS patients. Immunohistochemistry was used to compare the expression profile of GAD1 between OS and matched neighboring tissues. The potential antitumor effects of 3-MPA on cell viability, colony formation and the cell cycle were examined. Moreover, the in vivo effect of 3-MPA on tumor growth was investigated using tumor-bearing nude mice.

RESULTS

The expression level of GAD1 was aberrantly upregulated in OS tissues, but almost no expression of GAD1 was found in matched neighboring tissues. Western blotting analyses showed upregulation of GAD1 in OS cells compared to human osteoblast cells. In vitro and in vivo, 3-MPA significantly suppressed the growth of OS. Regarding the mechanism, 3-MPA inhibited β-catenin and cyclin D1 in OS cells, thereby inactivating the Wnt/β-catenin pathway.

CONCLUSIONS

OS displays increased expression of the GABAergic neuronal marker GAD1, and 3-MPA significantly reduces OS growth by inhibiting the Wnt/β-catenin pathway.

摘要

背景

作为γ-氨基丁酸能系统的标志物，谷氨酸脱羧酶1（GAD1）的表达主要局限于中枢神经系统。新兴研究表明，GAD1在肿瘤组织中的异常表达可能促进肿瘤细胞生长。GAD1在骨肉瘤（OS）发生发展中的作用仍不清楚，因此本研究旨在探究GAD1的表达状况及其特异性抑制剂3-巯基丙酸（3-MPA）对骨肉瘤的影响。

方法

使用R2数据库分析骨肉瘤患者中GAD1表达与临床预后的关系。采用免疫组织化学法比较骨肉瘤组织与其配对的相邻正常组织中GAD1的表达情况。检测3-MPA对细胞活力、集落形成和细胞周期的潜在抗肿瘤作用。此外，利用荷瘤裸鼠研究3-MPA对肿瘤生长的体内作用。

结果

骨肉瘤组织中GAD1的表达水平异常上调，但在配对的相邻正常组织中几乎未检测到GAD1的表达。蛋白质免疫印迹分析显示，与人类成骨细胞相比，骨肉瘤细胞中GAD1表达上调。在体外和体内，3-MPA均显著抑制骨肉瘤的生长。机制方面，3-MPA抑制骨肉瘤细胞中的β-连环蛋白和细胞周期蛋白D1，从而使Wnt/β-连环蛋白信号通路失活。

结论

骨肉瘤中γ-氨基丁酸能神经元标志物GAD1表达增加，3-MPA通过抑制Wnt/β-连环蛋白信号通路显著降低骨肉瘤的生长。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73cf/11128529/edc0a89071a6/mmcfigs11.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73cf/11128529/edc0a89071a6/mmcfigs11.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73cf/11128529/3316f807614e/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73cf/11128529/0aaac05e7c9c/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73cf/11128529/451312c620ec/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73cf/11128529/05fbe26ffe35/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73cf/11128529/05ed46e1ec47/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73cf/11128529/8e70cebe5fb5/mmcfigs1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73cf/11128529/4a784ca54983/mmcfigs2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73cf/11128529/2892344b8191/mmcfigs3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73cf/11128529/8a3ed9c6b654/mmcfigs4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73cf/11128529/d43733be8653/mmcfigs5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73cf/11128529/9ebcd4a52cf4/mmcfigs6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73cf/11128529/7e6ca6dd3976/mmcfigs7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73cf/11128529/edb5eb641b00/mmcfigs8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73cf/11128529/42296a6276d6/mmcfigs9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73cf/11128529/ca94e97b5fba/mmcfigs10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73cf/11128529/edc0a89071a6/mmcfigs11.jpg

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